390535 Degradable Lipid Nanoparticles with Predictable in Vivo siRNA Delivery Activity

Thursday, November 20, 2014: 10:06 AM
International 6 (Marriott Marquis Atlanta)
Kathryn A. Whitehead, Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA and Daniel G. Anderson, Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA

One of the most significant challenges in the development of clinically-viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. To this end, we synthesized 1400 degradable lipidoids and evaluated their transfection ability and structure function activity. Here we show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations upon IV administration to mice (siRNA EC50 values as low as 0.01 mg/kg). Surprisingly, we identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. In this talk, we will identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.

Extended Abstract: File Not Uploaded
See more of this Session: Bionanotechnology for Gene and Drug Delivery I
See more of this Group/Topical: Nanoscale Science and Engineering Forum